Rheumatoid Arthritis (RA), a prototypical systemic hyper-inflammatory autoimmune disease, is an excellent model in which to study the interplay between pathologic immunity and heart disease. People with RA have markedly increased mortality (primarily from heart disease) compared to the general population. Key findings from the first funding cycle include: i) the mortality gap between RA and the general population has widened in recent decades; ii) myocardial infarction (Ml) is more common and more likely to be silent in RA; iii) indicators of RA disease activity/severity and inflammation are significant independent predictors of Ml; and iv) RA subjects have less extensive coronary artery atherosclerosis and more coronary inflammation (at autopsy) than controls. Our results generated new insights regarding the important role of immune mechanisms underlying heart disease in the context of autoimmunity and also pointed towards our next research directions. In particular, our preliminary studies showed a large and unexplained excess risk for heart failure (HF) with a major impact on mortality among RA subjects. Hence, the goal of this application is to elucidate the nature and determinants of HF in RA by studying the spectrum of ventricular disease, from silent preclinical ventricular dysfunction to overt clinical HF. We will: i) prospectively assess (by echocardiogram) preclinical ventricular dysfunction (diastolic and/or systolic) in RA compared to non-RA subjects; ii) determine (among RA subjects) the proportion of the risk for ventricular dysfunction explained by RA disease characteristics, serum measures of autpimmunity/inflammation and immune response signatures (assessed using multiplex cytokine analysis); iii) investigate the role of immune-modulating drugs i.e.: TNF inhibitors, methotrexate, glucocqrticoids; and iv) determine whether HF in RA subjects has a different clinical profile than HF in non-RA subjects. Our proposal advances our previous work in a number of innovative new directions. Our finding suggesting autoantibodies as predictors of HF (even in the absence of autoimmune disease) is a novel concept that may hold important mechanistic clues. The introduction of immune response signatures is an innovative translational approach to understanding the immune phenotype of HF in RA subjects and may lead to novel predictors. In addition, this proposal effectively leverages the expertise and resources of other NIH-funded epidemiological investigations of ventricular dysfunction and HF in Olmsted County (HL55502 and HL 72435). This allows us to draw appropriate population-based comparison groups from the same underlying community at an overall cost saving to this application. Findings emanating from this study will improve our understanding of the pathways leading to HFin RAand shed light on the root causes of immune-mediated HFin the general population. Such knowledge is also the essential first step towards the important goal of decreasing the excess death rate among persons withRA. Public Health Relevance: Heart failure is an irreversible, fatal condition. People with rheumatoid arthritis have a high risk of heart failure. We will use echocardiograms, and tests of immunity in order to identify early signs of heart failure (in persons with Rheumatoid Arthritis) at a time when it may be treatable.